[Show abstract][Hide abstract] ABSTRACT: Envenomation by heamotoxic snakes constituted a critical health occurrence in the world. Bleeding is the most sever consequence following snake bite with viperid and crothalid snakes. It is believed that the degradation of vascular membrane caused hemorrhage; in contrast, some suggested that direct cytotoxicity has role in endothelial cell disturbances. This study was carried out to evaluate the direct toxicity effect of V. lebetina crude venom on Human Umbilical Vein Endothelial Cells (HUVECs).
The effect of V. lebetina snake venom on HUVECs growth inhibition was determined by MTT assay and neutral red uptake assay. The integrity of cell membrane through LDH release was measured with the Cytotoxicity Detection Kit. Morphological changes of endothelial cells were also evaluated using a phase contrast microscope.
In MTT assay, crude venom showed a cytotoxic effect on endothelial cells which was confirmed by the effect observed with neutral red assay. Also, crude venom caused changes in the integrity of cell membrane by LDH release. The morphological alterations enhanced in high concentration results in total cells number reduced.
V. lebetina venom showed potential direct cytotoxic effects on human endothelial cells in a manner of concentration- dependent inhibition.
Iranian journal of pharmaceutical research (IJPR) 12/2015; 14(Suppl):109-114. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The isolated perfused rat liver (IPRL) model has been used into toxicology study of rat liver. This model provides an opportunity at evaluation of liver function in an isolated setting. Studies showed that Cd, in a dose-dependent manner, induced toxic effects in IPRL models, and these effects were associated with aminotransferase activity and lipid peroxidation. The aim of this study was to investigate whether Mg and/or Se could have protective effects against the Cd toxicity in the IPRL model. Male Wistar rats (9-10 weeks) weighing 260-300 gr were used in this study. They were randomly divided into 8 groups of 4-6 rats per cage. In group 1, liver was perfused by Krebs-Henseleit buffer without MgSO4 (Control). Groups 2-8 were exposed to Mg, Se, Cd, Mg +Se, Cd + Mg, Cd + Se, Cd + Mg + Se respectively in Krebs-Henseleit buffer with no added MgSo4. Biochemical changes in the liver were examined within 90 minutes, and the result showed that the exposure to Cd, lowered glutathione level, while it increased malondialdehyde level and aminotransferase activities in IPRL model. Mg administration during exposure to Cd reduces the toxicity of Cd in the liver isolated while Se administration during exposure to Cd did not decrease Cd hepatotoxicity. Nevertheless, simultaneous treatment with Se and Mg on Cd toxicity have strengthened protective effects than the supplementation of Se alone in the liver.
[Show abstract][Hide abstract] ABSTRACT: Hyperglycemia is widely recognized as the underlying cause for some debilitating conditions in diabetic patients. The role of cannabinoid CB1 and vanilloid TRPV1 receptors and their endogenous agonists, endovanilloids, in diabetic neuropathy is shown in many studies. Here we have used PC12 cell line to investigate the possible influence of glucose concentration in culture medium on cytoprotective or toxic effects of a CB1 [WIN55 212-2 (WIN)], or TRPV1 [Capsaicin (CAS)] agonist.
Cell viability was tested using the MTT assay. We have also measured TRPV1 and CB1 transcripts by real time reverse transcription-polymerase chain reaction while cells were grown in low (5.5 mM) and high (50 mM) glucose concentrations.
Real time PCR results indicated that high glucose medium increased (P<0.01) TRPV1 mRNA and decreased (P <0.001) that of CB1. Cell culture tests show that hyperglycemic cells are more vulnerable (Dose × Medium, F (3,63)=41.5, P<0.001) to the toxic effects of capsaicin compared to those grown in low glucose medium.
These findings propose that hyperglycemic conditions may result in neuronal cell death because of inducing a counterbalance between cytotoxic TRPV1 and cytoprotective CB1 receptors.
Iranian Journal of Basic Medical Sciences 09/2014; 17(9-9):673-678. · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100 mg/kg of metformin twice daily for 14 days. Isoproterenol (100 mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LV dp/dtmax and LV dp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50 mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-α and IL-6. However, the lower doses of 25 and 50 mg/kg were more effective than 100 mg/kg. Phosphorylated AMPKα (p-AMPK) in the myocardium was significantly elevated by 25 mg/kg of metformin, slightly by 50 mg/kg, but not by 100 mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium.
European Journal of Pharmacology 08/2014; 737:77–84. DOI:10.1016/j.ejphar.2014.05.003 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they posses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR) A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample were collected to measure urea and creatinin level. Also kidneys were removed for histopatological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta ( IL-1β) and iNOS and improved histopathalogical damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have elicit any effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.
European Journal of Pharmacology 06/2014; 738. DOI:10.1016/j.ejphar.2014.05.050 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective(s):
In recent years, there has been an increasing amount of study on early diagnosis of kidney injury through sensitive and specific biomarkers. We examined the practical applicability of the urinary levels of NAG (N-acetyl-β-D-glucosaminidase), AP (alkaline phosphatase), and LDH (lactate dehydrogenase) as renal dysfunction screening biomarkers in full and pre-term newborns treated with gentamicin.
Materials and Methods:
Fourteen pre-term and fifteen full-term newborns who received gentamicin for suspected infections were enrolled. Serum and urine specimens were obtained before the zero days and after gentamicin infusion on the 1st, 3rd, and 5th days of treatment.
In full-term newborns a significant increase in urinary NAG, LDH, AP after 5 days of gentamicin administration compared with control group was noted (P<0.05, P<0.001 and P<0.01; respectively).
Our findings indicate that urinary enzymes may be useful in full-term newborns as a non-invasive method for evaluation of tubular function.
Iranian Journal of Basic Medical Sciences 05/2014; 17(5):391-5. · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative damage has been implicated in disorders associated with abnormal copper metabolism and also Cu(2+) overloading states. Besides, mitochondria are one of the most important targets for Cu(2+), an essential redox transition metal, induced hepatotoxicity. In this study, we aimed to investigate the mitochondrial toxicity mechanisms on isolated rat liver mitochondria. Rat liver mitochondria in both in vivo and in vitro experiments were obtained by differential ultracentrifugation and the isolated liver mitochondria were then incubated with different concentrations of Cu(2+). Our results showed that Cu(2+) induced a concentration and time-dependent rise in mitochondrial ROS formation, lipid peroxidation, and mitochondrial membrane potential collapse before mitochondrial swelling ensued. Increased disturbance in oxidative phosphorylation was also shown by decreased ATP concentration and decreased ATP/ADP ratio in Cu(2+)-treated isolated mitochondria. In addition, collapse of mitochondrial membrane potential (MMP), mitochondrial swelling, and release of cytochrome c following of Cu(2+) treatment were well inhibited by pretreatment of mitochondria with CsA and BHT. Our results showed that Cu(2+) could interact with respiratory complexes (I, II, and IV). This suggests that Cu(2+)-induced liver toxicity is the result of metal's disruptive effect on liver hepatocyte mitochondrial respiratory chain that is the obvious cause of Cu(2+)-induced ROS formation, lipid peroxidation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.
[Show abstract][Hide abstract] ABSTRACT: pH-responsive docetaxel-conjugated poly (lactic acid) (PLA)-polyethyleneglycol (PEG) micellar formulation was synthesized via acid labile hydrazone linkage. Levulinic acid (LEV) was used as a linker between docetaxel (DTX) and hydrazine. Targeted delivery of DTX was achieved by conjugation of folate to PEG segment. The DTX conjugated polymeric micelles were about 181nm in diameter and their critical micelle concentration was 5.18μg/ml. DTX was released from micelles in a pH-dependent manner. The results showed a significant difference in DTX release from polymeric micelles at pH 5.0 and pH 7.4. Cytotoxicity assays using methyl tetrazolium (MTT), neutral red (NR) and lactate dehydrogenase (LDH) demonstrated a decreased cytotoxic activity of the drug containing nanoconjugate compared with free DTX that appears to be contributed to the sustained release of drug from micelles. Based on these results, it is expected that this pH-responsive nanoconjugate is promising as a useful carrier for targeted delivery of anticancer agents.
[Show abstract][Hide abstract] ABSTRACT: Occupational inhalation exposure to noxious agents is not uncommon. Herein, we present a 26-year-old male student who had accidental acute inhalation exposure to a large quantity of titanium ethanolate and hydrogen chloride in chemistry lab. He was referred to the emergency department of our hospital with low-grade fever, dyspnea, headache, fatigue and myalgia. After 24 hrs of symptomatic treatment (oxygen therapy and acetaminophen), the fever was subsided and the patient discharged home in a good clinical condition. The presented symptoms could be interpreted as a form of metal fume fever. It can therefore be concluded that organo-metallic compound of titanium metal may have the potential to produce metal fume fever in human.
International Journal of Occupational and Environmental Medicine 04/2014; 5(2):106-8.
[Show abstract][Hide abstract] ABSTRACT: Selective delivery of anticancer agents to target areas in the body is desirable to minimize the side effects while maximizing the therapeutic efficacy. Anthracycline antibiotics such as doxorubicin (DOX) are widely used for treatment of a wide variety of solid tumors.This study evaluated the potential of a polymeric micellar formulation of doxorubicin as a nanocarrier system for targeted therapy of a folate-receptor positive human ovarian cancer cell in line.
DOX-conjugated targeting and non-targeting micelles prepared by the dialysis method were about 188 and 182 nm in diameter, respectively and their critical micelle concentration was 9.55 mug/ ml. The DOX-conjugated micelles exhibited a potent cytotoxicity against SKOV3 human ovarian cancer cells. Moreover, the targeting micelles showed higher cytotoxicity than that of non-targeting ones (IC50 = 4.65 mug/ml vs 13.51 mug/ml).
The prepared micelle is expected to increase the efficacy of DOX against cancer cells and reduce its side effects.
DARU-JOURNAL OF FACULTY OF PHARMACY 03/2014; 22(1):30. DOI:10.1186/2008-2231-22-30 · 1.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Ionizing radiation interacts with biological systems to induce excessive fluxes of free radicals that attack various cellular components. Melatonin has been shown to be a direct free radical scavenger and indirect antioxidant via its stimulatory actions on the antioxidant system.The aim of this study was to evaluate the antioxidant role of melatonin against radiation-induced oxidative injury to the rat liver after whole body irradiation.
Materials and Methods: In this experimental study,thirty-two rats were divided into four groups. Group 1 was the control group, group 2 only received melatonin (30 mg/kg on the first day and 30 mg/kg on the following days), group 3 only received whole body gamma irradiation of 10 Gy, and group 4 received 30 mg/kg melatonin 30 minutes prior to radiation plus whole body irradiation of 10 Gy plus 30 mg/kg melatonin daily through intraperitoneal (IP) injection for three days after irradiation. Three days after irradiation, all rats were sacrificed and their livers were excised to measure the biochemical parameters malondialdehyde (MDA) and glutathione (GSH). Each data point represents mean ± standard error on the mean (SEM) of at least eight animals per group. A one-way analysis of variance (ANOVA) was performed to compare different groups, followed by Tukey’s multiple comparison tests (p<0.05).
Results: The results demonstrated that whole body irradiation induced liver tissue damage by increasing MDA levels and decreasing GSH levels. Hepatic MDA levels in irradiated rats that were treated with melatonin (30 mg/kg) were significantly decreased, while GSH levels were significantly increased, when compared to either of the control groups or the melatonin only group.
Conclusion: The data suggest that administration of melatonin before and after irradiation may reduce liver damage caused by gamma irradiation.
Keywords: Radiation, Lipid peroxidation, MDA, GSH
[Show abstract][Hide abstract] ABSTRACT: Arsenic exposure mainly through food and water has been shown to be associated with increased incidence of numerous cancers and non-cancer harmful health. It is also used in cancer chemotherapy and treatment of several cancer types due to its apoptogenic effects in the various cancer and normal cell lines. We have already reported that liver is the storage site and important target organ in As (III) toxicity and recently, it has been suggested that hepatic toxicity of arsenic could be resulted from impairment of the liver mitochondria. In this study, interaction of As (III) with freshly isolated rat mitochondria was investigated. We determined different mitochondrial toxicity factors as well as mitochondrial sources of ROS formation using specific substrates and inhibitors following addition of As (III) to the mitochondria. Our results showed that arsenic (III) increased mitochondrial ROS formation, lipid peroxidation and mitochondrial membrane potential collapse, cytochrome c release and mitochondrial swelling in a concentration dependent manner. Addition of As (III) in to the isolated mitochondria, inhibited complexes I and II leading to disruption of mitochondrial electron transfer chain, decreased mitochondrial ATP content and ROS formation.
Iranian journal of pharmaceutical research (IJPR) 11/2013; 12(Suppl):121-38. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Depleted uranium (DU) is widely used in military anti-armor weapons. Recent evidence suggested that oxidative stress and mitochondrial dysfunction may contribute to DU-induced toxicity. However, the underlying mechanisms of DU toxicity in mitochondria are not well understood. In this study, liver mitochondria were obtained from Wistar rats treated with DU in the form of uranyl acetate (UA) (0.5, 1 or 2 mg/kg i.p.) using differential centrifugation. For in vitro experiments, control rat liver mitochondria were incubated with different concentrations of UA (50, 100 or 200 μM) for 1 hr. Mitochondrial reactive oxygen species (ROS) production, collapse of mitochondrial membrane potential, and mitochondrial swelling were examined by flow cytometry. Mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Extent of lipid peroxidation (LPO) and glutathione (GSH) oxidation, and also complex II and IV activities were detected via spectroscopy. Further, the concentration of ATP and ATP/ADP ratio was measured using luciferase enzyme and release of cytochrome c from mitochondria which was detected by ELISA kit. UA induced succinate-supported mitochondrial ROS production, elevated LPO levels, GSH oxidation, and mitochondrial complex II inhibition. UA also induced mitochondrial permeability transition and increase in cytochrome c release which subsequently disturbed oxidative phosphorylation and reduced the mitochondrial ATP concentration. Data suggest that mitochondrial oxidative stress and uncoupling of oxidative phosphorylation may play key roles in DU-induced hepatic toxicity.
[Show abstract][Hide abstract] ABSTRACT: The isocyanates are widely used as precursors of polyurethane products, as well as carbamate insecticides. Toluene 2,4-diisocyanate (TDI) is one of the most important commercially used isocyanates. Humans may be exposed to TDI by inhalation, ingestion, dermal and eye contact. TDI is a powerful irritant to the mucosal membranes of the gastrointestinal and respiratory tracts, eyes and the skin. Pulmonary manifestations, especially occupational asthma, are the predominant manifestations after TDI toxicity. Herein, we present intestinal obstruction as an extraordinary manifestation of acute TDI toxicity after occupational exposure. TDI toxicity may cause intestinal obstruction.
International Journal of Occupational and Environmental Medicine 07/2013; 4(3):164-6.
[Show abstract][Hide abstract] ABSTRACT: Tropisetron, a selective 5-HT3 receptor antagonist, has been widely used to counteract chemotherapy-induced emesis. New investigations described immunomodulatory properties for tropisetron which may not be 5HT3R mediated. In the present study, we assessed the potential effects of tropisetron on an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization. Animals were treated with tropisetron (5mg/kg/day); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (10mg/kg/day); tropisetron (5mg/kg/day) plus mCPBG(10mg/kg/day), and granisetron (5mg/kg/day) intraperitoneally on days 3-35 post-immunization (pi). Treatment with tropisetron and granisetron markedly suppressed the clinical symptoms of EAE (P< 0.001) and reduced leukocyte infiltration as well as demyelination in spinal cord (P < 0.05). In addition, in vivo tropisetron, granisetron or tropisetron plus mCPBG therapy greatly reduced in vitro MOG35-55-stimulated proliferation of mononuclear cells (MNC) from spleens, and MOG35-55-induced IL-2, IL-6 and IL-17 production by splenocytes isolated from EAE-induced mice (P < 0.05). Concurrent administration of tropisetron and mCPBG did not significantly alter the histological damage in the spinal cord. mCPBG had no effect on the mentioned parameters. Taken together, these findings indicate that tropisetron has considerable immunoregulatory functions in EAE and may be promising for the treatment of MS or other autoimmune and inflammatory diseases of the CNS. Furthermore, beneficial effects of tropisetron in this setting seem to be both receptor dependent and receptor independent in the early phase of the disease.
[Show abstract][Hide abstract] ABSTRACT: Ionizing radiation interacts with biological systems to produce reactive oxygen species and reactive nitrogen species which attack various cellular components. Radio-protectors act as prophylactic agents to shield healthy cells and tissues from the harmful effects of radiation.
Past research on synthetic radio-protectors has brought little success, primarily due to the various toxicity-related problems. Results of experimental research show that antioxidant nutrients, such as vitamin E and herbal products and melatonin, are protective against the damaging effects of radiation, with less toxicity and side effects. Melatonin ameliorate the oxidative injuries due to ionizing radiation and is a potentially useful radioprotector. Moreover, based on radiobiological models we can hypothesize that melatonin may postpone the saturation of repair enzymes which leads to repairing more induced damage by repair system and more importantly allows the use of higher doses of radiation during radiation oncology to get a better therapeutic ratio. Therefore, we propose that, in the future, antioxidant radio-protective agents such as melatonin may improve the therapeutic index in radiation oncology treatments.
Iranian Congress of Nuclear Medicine, Shiraz, Iran; 05/2013
[Show abstract][Hide abstract] ABSTRACT: Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 μM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome.